Mechanism of lapatinib-mediated radiosensitization of breast cancer cells is primarily by inhibition of the Raf>MEK>ERK mitogen-activated protein kinase cascade and radiosensitization of lapatinib-resistant cells restored by direct inhibition of MEK

Sambade, Maria J.; Camp, J. Terese; Kimple, Randall J.; Sartor, Carolyn I.; Shields, Janiel M.

doi:10.1016/j.radonc.2009.09.006

« Previous Next »Radiotherapy & Oncology
Volume 93, Issue 3 , Pages 639-644, December 2009

Mechanism of lapatinib-mediated radiosensitization of breast cancer cells is primarily by inhibition of the Raf>MEK>ERK mitogen-activated protein kinase cascade and radiosensitization of lapatinib-resistant cells restored by direct inhibition of MEK

Maria J. Sambade
- Department of Radiation Oncology and
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, NC, USA
J. Terese Camp
- Department of Radiation Oncology and
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, NC, USA
Randall J. Kimple
- Department of Radiation Oncology and
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, NC, USA
Carolyn I. Sartor
- Department of Radiation Oncology and
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, NC, USA
Janiel M. Shields
- Department of Radiation Oncology and
- Department of Dermatology, University of North Carolina at Chapel Hill, NC, USA
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, NC, USA
- Corresponding author. Address: Department of Radiation Oncology, University of North Carolina, School of Medicine, LCCC Rm 12-048, CB 7295, Chapel Hill, NC 27599, USA.

Received 13 July 2009; received in revised form 25 August 2009; accepted 15 September 2009. published online 26 October 2009.

Abstract

Background and purpose

We recently showed that lapatinib, an EGFR/HER2 inhibitor, radiosensitized breast cancer cells of the basal and HER2+ subtypes. The purpose of this study was to identify the downstream signaling pathways responsible for lapatinib-mediated radiosensitization in breast cancer.

Materials and methods

Response of EGFR downstream signaling pathways was assessed by Western blot and clonogenic cell survival assays in breast tumor cells after irradiation (5Gy), lapatinib, CI-1040, or combined treatment.

Results

In SUM102 cells, an EGFR+ basal breast cancer cell line, exposure to ionizing radiation elicited strong activation of ERK1/2 and JNK, which was blocked by lapatinib, and weak/no activation of p38, AKT or STAT3. Direct inhibition of MEK1 with CI-1040 resulted in 95% inhibition of surviving colonies when combined with radiation while inhibition of JNK with SP600125 had no effect. Lapatinib-mediated radiosensitization of SUM102 cells was completely abrogated with expression of constitutively active Raf. Treatment of lapatinib-resistant SUM185 cells with CI-1040 restored radiosensitization with 45% fewer surviving colonies when combined with radiation.

Conclusions

These data suggest that radiosensitization by lapatinib is mediated largely through inhibition of MEK/ERK and that direct inhibition of this pathway may provide an additional avenue of radiosensitization in EGFR+ or HER2+ breast cancers.

Keywords: EGFR, Lapatinib, CI-1040, MEK/ERK, Resistance, Breast cancer